The goal of this Project is the better understanding of the relationship of basal cell carcinomas (BCCs) to tissue stem cells, utilizing the Ptch1 mouse model of BCC carcinogenesis as a robust research tool of real relevance to human skin cancer and more broadly to skin biology and tumorigenesis. This application is a direct outgrowth of our own NIH-funded studies of BCC carcinogenesis in these mice as well as of the insights of others that have occurred during the past half-decade. Based on these results we propose herein a set of experiments designed to address two important questions - (i) What is the cell of origin of BCCs? This is a question which, to our knowledge, has not been answered directly and experimentally for any cancer for the carcinogeneic process in vivo (ii) Are the cells of a BCC heterogeneous in their capacity for self-renewal? We propose a set of ambitious studies which are of a scope commensurate with these questions, which we are confident are sufficiently powerful to answer the questions, and which are so inter-related that there is a real synergy in addressing all of them together. We are able to propose these studies because of our long-standing interest and expertise in BCC carcinogenesis and, especially, because new techniques and approaches just now for the first time make these studies possible.